- Email: [email protected]
Wounds, burns, trauma, and injury
Accepted Manuscript Title: Wounds, Burns, Trauma, and Injury Author: Marianne Frieri Krishan Kumar Anthony Boutin PII: DOI: Reference:
S2213-9095(16)30004-0 http://dx.doi.org/doi:10.1016/j.wndm.2016.02.004 WNDM 72
To appear in: Received date: Accepted date:
17-2-2016 21-2-2016
Please cite this article as: Marianne Frieri, Krishan Kumar, Anthony Boutin, Wounds, Burns, Trauma, and Injury, Wound Medicine http://dx.doi.org/10.1016/j.wndm.2016.02.004 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Wounds, Burns, Trauma, and Injury
Marianne Frieri, M.D., Ph.D1, Krishan Kumar, M.D2, Anthony Boutin, M.D3. Division of Allergy Immunology1, Department of Medicine,1 Division of Pediatric2 and Adult Emergency Medicine3, Department of Emergency Medicine 2,3 Nassau University Medical Center 2201 Hempstead Turnpike, East Meadow, NY 11554 Krishan Kumar, M.D,,telephone :516-567-9855, fax: 516-572-54 65 .email: [email protected] Anthony Boutin, M.D.telephone:516-572-6175, fax: 516-572-5465 email:[email protected] Address corrrespondence to Marianne Frieri, M.D., Ph.D Nassau University Medical Center, Department of Medicine 2201 Hempstead Turnpike, East Meadow, New York, 11554 Telephone:516-572-6501,fax:516-572 5609,email:[email protected]
Abstract: The purpose of this review paper is to discuss many areas related to wounds, photobiomodulation, reactive oxygen species, biofilms, neutrophils in wounds, other cells and growth factors in wounds, T cells in wounds, additional role of stem cell in wounds, mast cells in wounds, trauma and injury, surgical management, burns, trauma and injury, cytokines and trauma
Key words: wounds, burns, photobiomodulation, biofilms, trauma, injury
Introduction Wounds: In wound healing, fibroblasts collagen and matrix deposition are important for healing, however this material can contribute to remodeling of organs with substantial morbidity and mortality.[1] Certain receptors can lead to fibroblast activation, collagen synthesis and adenosines, a small molecule extracellularly generated from adenine nucleotides from direct stimulation, hypoxia, or injury can act via a family of classical seven-pass G protein-coupled protein receptors as discussed in a recent article.[1] Signaling pathways are involved with adenosine receptors and in wound healing as described in this recent article [1] Adenosine and its receptors play important roles in both production of matrix and neovascularization, critical areas for wound healing and tissue repair. These receptors are A2A and A2B, with generation of cAMP and activation of downstream targets such as protein kinase A and exchange protein activated by cAMP or EPAC, a family of guanine nucleotide exchange factors can cause activation of fibroblast and also collagen synthesis.[1]. Adenosine signaling contributes to fibrosis and may have opposite effects in a variety of different organs. Thus, drug development that selectively target these receptors and signaling pathways will disrupt fibrosis pathogenesis and slow or arrest the progression of important underlying disorders.. In a recent article these authors reported on the development of an image-based multi-scale mechanical model that predicts the short-term structural reorganization of a fibrin gel by fibroblasts.[2] Regional differences in short-term structural remodeling and cell migration were observed for two gel boundary conditions. A pilot experiment indicated that these small differences in the short-term remodeling of the fibrin gel translated into substantial differences in long-term remodeling for collagen production.[2] The multi-scale models predicted some
regional differences in remodeling and qualitatively similar reorganization patterns for the two boundary conditions. However, other aspects of the model, magnitudes and rates of deformation of gel did not match the experiments. These discrepancies between model and experiment can be important for challenging model assumptions and devising new experiments enhancing the understanding of how this multi-scale system functions. Thus, these efforts can improve the predictions of remodeling, dermal wound healing and reduction of patient scarring. These models could be used to recommend patient-specific mechanical-based treatment dependent on s wound geometry, location, age, and health.[2] A study aimed to develop optimal amikacin dosing for the empirical treatment of Gram-negative bacterial sepsis in pediatric patients with burn injuries.[3] Optimal amikacin dosing regimens for the empirical treatment of Gram-negative bacterial sepsis in pediatric patients with burn injuries were developed. [3] The authors stated amikacin pharmacokinetics are altered in patients with burn injuries, including a significant increase in clearance and the volume of distribution in simulations, increased doses (≥25 mg/kg) led to improved PD target attainment rates. Further clinical evaluation of this proposed dosing regimen is warranted to assess clinical and microbiological outcomes in pediatric patients with burn wound sepsis. [3]
Photobiomodulation: Treatments for many wounds can be recalcitrant and an area of photobiomodulation involves inducing wound healing by illuminating wounds with light emitting diodes or lasers. [4] Photobiomodulation is used on different animal models, in vitro studies, and clinically. Wound healing is induced by many different wavelengths and powers with no optimal set of parameters. [4] Simultaneous multiple wavelength illumination according to data suggest it is more
efficacious than single wavelengths, and the optimal single and multiple wavelengths must be better defined to induce more reliable and extensive healing of different wound types. These authors focused on studies in which specific wavelengths could induce wound healing and on their mechanisms. [4] Reactive Oxygen Species: Photobiomodulation is defined as a nonthermal process involving endogenous chromophores that are able to elicit photophysical and photochemical events at various scales, resulting in beneficial photobiological responses. There appears to be enough anecdotal scientific literature for the use of light in wound care from sterilization, desiccation, promotion of healing and effective treatment for a number of conditions, including inflammation.[5] In terms of the mechanism of photobiomodulation, interaction of light and biological tissues can lead to generation of transient and extremely reactive chemical intermediates, or reactive oxygen species (ROS), in both extracellular and intracellular compartments. [5] The different materials, sizes, shapes, and structures have different responses. This paper investigated the successful treatments made with nanoparticles and some general health effects. A review of the literature revealed an inflammatory response and an increased production of ROS, common immune responses to nanomaterial use. The mechanisms by which the inflammatory response and ROS production was discussed.[6] Quinones are electron proton carriers that play a primary role in the aerobic metabolism of virtually every cell. Quinones undergo highly regulated redox reactions in the mitochondria, Golgi apparatus, plasma membrane and endoplasmic reticulum. Important consequences of these electron transfer reactions are the production of and protection against ROS. Quinones have been
extensively studied for both their cytotoxic as well as cellular protective properties and they have been particularly useful in rational drug design. [7] A severe burn is associated with release of inflammatory mediators which ultimately cause local and distant pathophysiological effects. [8] Mediators including ROS and Reactive Nitrogen Species (RNS) are increased in affected tissue, which are implicated in pathophysiological events observed in burn patients.[8] However following a burn, there is an enormous production of ROS which is harmful and implicated in inflammation, SIRS, immunosuppression, infection and sepsis, tissue damage and multiple organ failure. Thus, clinical response to burn is dependent on the balance between production of free radicals and its detoxification. Supplementation of antioxidants in human and animal models has proven benefit in decreasing distant organ failure suggesting a cause and effect relationship. Oxidative damage is one of the mechanisms responsible for the local and distant pathophysiological events observed after burn, and therefore anti-oxidant therapy might be beneficial in minimizing injury in burned patients. [8] Biofilms A beneficial effect of low-level laser therapy in promoting wound healing in both animal and human studies has been demonstrated.[9] This recent review identified literature reporting on low-level laser therapy alone, without photodynamic agents, as an antimicrobial/antibiofilm technology and determined its effects on wound healing.[9] The authors stated efforts need to be addressed to standardize phototherapy and develop suitable in vitro and in vivo biofilm models to test low-level laser therapy efficacy in promoting biofilm eradication and wound healing.[9] Biofilms due to Staphylococcus aureus and exotoxins that act as superantigens have been implicated to play an important pathological role in the incidence, maintenance, and ongoing burden of chronic rhinosinusitis as well as in wounds. [10] A better understanding of the
interplay between bacterial factors, host factors, and the environment will facilitate better management. This literature review focused on these factors and highlights current research in this field that could relate to wounds.[10] Biofilm growth is associated with an increased in mutations. Infection in the form of biofilm may have an important role in the maintenance of the recalcitrant inflammation for not only chronic sinusitis but could relate to wound healing, also a common chronic condition.[11].Bacterial biofilms are resistant to antibiotics, disinfectants, phagocytosis and other components of the innate and adaptive inflammatory defense system.[12] Antibiotic resistance is enhanced by the ability of resident bacteria cells to share genetic material within the biofilm structure, thus facilitating the persistence of antibiotic-resistant genes.[12] These authors stated biofilms can be prevented by antibiotic prophylaxis or early aggressive antibiotic therapy as in wounds and treated by chronic suppressive antibiotic therapy. Promising strategies may include the use of compounds which can dissolve the biofilm matrix and increases biofilm susceptibility to antibiotics and phagocytosis.[12] Biofilms can affect chronic wound healing due to the production of destructive enzymes and toxins that can lead to a chronic inflammatory state. They also can be polymicrobial and can result in delayed wound healing with chronic wound infection resistant to antibiotics. The authors of this recent article suggest that biofilms are a major player in the chronicity of wounds and they are a complex concept to diagnose and management.[13] An animal study was evaluated on the impact of a novel, antimicrobial dressing on Pseudomonas aeruginosa biofilm-infected wounds.[14] This dressing consistently decreased P. aeruginosa bacterial counts and improved wound healing. The authors stated this study was the first quantifiable and consistent in vivo evidence of a topical antimicrobial dressing's impact against
established wound biofilm and the development of clinically applicable therapies against biofilm related to this area s is critical to improving chronic wound care.[14] This recent animal study demonstrated that oxygen consumption by biofilms and by the responding leukocytes, may impede wound healing by depleting the oxygen required for healing. These results supported the hypothesis that bacterial biofilms in chronic wounds lead to chronicity by contributing to maintenance of localized low oxygen tensions, through their metabolic activities and their recruitment of cells that consume oxygen for the processes related host defensive.[15] Photobiomodulation has been noted to promote platelet aggregation and activation in the inflammatory phase, it is also known to promote proliferation and degranulation of mast cells [16] In the proliferative phase, photobiomodulation promotes proliferation of cells such as fibroblasts, keratinocytes, osteoblasts, and chondrocytes and induces matrix synthesis.[17] The antiinflammatory effects of photobiomodulation therapy are direct effects on both pro- and antiinflammatory factors, such as IL-1, IL-8, Cox1, and Cox 2. others. [18][19] The objective of this study was to decrease adherence of wounds of commercial silver based wound dressings using a non-adherent layer.[20] This non-adherent layer was thought to lower the dressing's adherence to burn wounds with no compromise on antimicrobial activity or increase in the cytotoxicity. A grafted polyacrylamide served as the non-adherent layer and dressing adherence was measured with an other published in vitro gelatin model. The dressings were challenged with two clinically retrieved bacterial strains of Methicillin-resistant Staphylococcus aureus and multidrug resistant Pseudomonas aeruginosa with both a disk diffusion test, and antibacterial test suspension.[20] It was noted by the authors that fibroblast
survival was improved by the polyacrylamide grafting and that the polyacrylamide as a nonadherent layer significantly decreased the adherence of these two commercial antimicrobial dressings in an in vitro gelatin model while preserving their antimicrobial efficacy, thus reducing cytotoxicity.[20] Excessive scars, such as keloids and hypertrophic scars result from aberrations in physiologic wound healing and an exaggerated inflammatory process is one of the main pathophysiological issues.[21] Scars can lead to pain, pruritis, limit joint mobility, and cause a range of cosmetic deformities affecting the patient's quality of life and extensive research has been done on hypertrophic scar and keloid formation resulting in the many treatments and prevention methods. [21] Mesenchymal stem cells, among their multifunctional roles, are known regulators of inflammation and are a major candidate for cell therapy to treat or prevent excessive scars. This paper reviewed extensively research examining the mechanism and potential of stem cell therapy in the treatment of excessive scars. [21] Neutrophils in Wounds: Neutrophils are important inflammatory cells. They arrive at the wound through chemotaxis, traversing postcapillary venules to degrade pathogens with granules within phagolysosomes, and lead to cell death or apoptosis.[22] IL-10 secreted by mesenchymal stem cells inhibit neutrophil invasion into the wound. Mesenchymal stem cells secrete TNF-stimulated gene/protein-6 (TSG6),which interacts with protein ligands inhibiting rolling and neutrophil transendothelial migration. Dyer noted that TSG-6 interacts with the glycosaminoglycan binding site of CXCL8 (IL-8), a chemokine produced by macrophages and transported to the surface of the endothelium, impairing neutrophil adhesion and migration.[22]
Chronic non-healing wounds are a significant bothersome area to patients and can result in severe complications.[23] Handling of chronic, non-healing wounds can be discouraging due to lack of improvement, and a recent explanation can be involvement of biofilm infections in the pathogenesis of non-healing wounds. Autologous leucopatches are a new, adjunctive therapeutic option, with promising clinical effects and a major contribution is believed to result from the release of stimulating growth factors from activated thrombocytes within the leucopatch.[23] Leucopatches contain substantial number of leucocytes and the aim of the present study was to investigate the activity of the polymorphonuclear neutrophils (PMNs) within the leucopatch. The authors showed significant PMN respiratory with active phagocytosis and killing of Pseudomonas aeruginosa by the leucopatch. Bacterial induced migration of PMNs from the leucopatch, and uptake of P. aeruginosa by PMNs within the leucopatch developed. This study substantiated that the beneficial clinical effect in chronic wounds by leucopatches is attributed to the activity of the PMNs within the leucopatch.[23] Although the definitive process underlying such scar formation is yet to be elucidated, the upregulated, exaggerated inflammatory response has been found to be a critical step in achieving excessive scars.[24][25] Other Cells and Growth Factors Involved in Wounds: Normal physiologic wound healing in adults undergoes three overlapping phases: inflammation, proliferation, and remodeling.[26] After injury, platelet degranulation and activation of complement and coagulation cascades result in formation of a fibrin clot at the site of injury. This structure provides hemostasis and functions as the seat of wound chemotaxis. This temporary extracellular matrix (ECM) stimulates recruitment of inflammatory cells such as neutrophils, macrophages, epithelial cells, mast cells, endothelial cells, and fibroblasts, which in turn produce proinflammatory mediators including macrophage inflammatory protein- 1alpha
(MIP-1ߙ), monocyte chemotactic protein-1 (MCP- 1), RANTES, interleukin-1beta (IL-1ߚ), and interleukin-6.[27][28] Inflammatory cells deliver a wide range of growth factors, such as transforming growth factorbeta 1 (TGF-ߚ1), transforming growth factor-alpha (TGF-ߙ), basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF), and platelet derived growth factor (PDGF) . [29] T Cells in Wounds: T regulatory cells or Tregs, produce specific effector cytokines under unique transcriptional regulation. Burn injury can induce global changes to the systemic immune response, including suppressed immune function and increased susceptibility to infection and, burn trauma is associated with remote organ injury. After postburn injury, a decreased Th17/Th1 ratio could contribute to increased susceptibility to extracellular pathogens. In this article, the authors showed that Tregs facilitate cutaneous wound healing. Tregs that accumulate in the skin early after wounding, and specific ablation of these cells has resulted in delayed wound re-epithelialization and kinetics of wound closure.[30] Tregs in wounded skin also attenuated IFN-γ production and proinflammatory macrophage accumulation. Tregs also induce expression of the epidermal growth factor receptor (EGFR) upon wounding. However lineage-specific deletion of EGFR in Tregs resulted in reduced Treg accumulation and activation in wounded skin, delayed wound closure, and increased proinflammatory macrophage accumulation. The results of this study revealed a novel role for Tregs in facilitating skin wound repair and suggest the use the EGFR pathway to mediate these effects.[30]
Additional Role of Stem Cell in Wounds: Mesenchymal stem cells, among their multifunctional roles, are known regulators of inflammation and have been receiving attention as a major candidate for cell therapy to treat or prevent excessive scars. This paper extensively reviewed the body of research examining the mechanism and potential of stem cell therapy in the treatment of excessive scars.[31] With the discovery of adipose stem cells (ASCs), 40 years after the identification of bone marrow stem cells, a new era of active stem cell therapy has opened. [32] ASCs are already clinically applied in many other purposes such as cell-enriched lipotransfer, wound healing, skin rejuvenation, scar remodeling and skin tissue engineering. Researches have disclosed some of their unique functions as mesenchymal stem cells. There have been increasing numbers of scientific reports on the therapeutic effect of ASCs on skin repair, scar remodeling and rejuvenation. Wound healing and scar remodeling are complex, multi-cellular processes that involve coordinated efforts of many cell types and various cytokines reports showed ASCs as a powerful source of skin regeneration because of their capability to provide not only cellular elements, but also numerous cytokines. Currently, other attractive functions of ASCs in the recovery of extrinsic aging and radiation damage are under active investigation. It seems that autologous ASCs have great promise for applications in repair of skin, rejuvenation of aging skin and aging-related skin lesions. This review focused on the specific roles of ASCs in skin tissue, especially related with wound healing, radiation injury, scar remodeling, skin rejuvenation and skin engineering.[32] Recently, stem cell therapy has emerged as a new approach to accelerate wound healing. [33] Adipose-derived stem cells (ASCs) hold great promise for wound healing, because they are multipotential stem cells capable of differentiation into various cell lineages and secretion of
angiogenic growth factors. The aim of this study was to evaluate the benefit of ASCs on wound healing and then investigate the probable mechanisms.[33] ASCs characterized by flow cytometry were successfully isolated and cultured. An excisional wound healing model in rat was used to determine the effects of locally administered ASCs. The gross and histological results showed that ASCs significantly accelerated wound closure in normal and diabetic rat, including increased epithelialization and granulation tissue deposition.The authors applied GFPlabeled ASCs on wounds to determine whether ASCs could differentiate along multiple lineages of tissue regeneration in the specific microenvironment. Immunofluorescent analysis indicated that GFP-expressing ASCs were costained with pan-cytokeratin and CD31, indicating spontaneous site-specific differentiation into epithelial and endothelial lineages. These data suggested that ASCs not only contribute to cutaneous regeneration, but also participate in new vessels formation. Moreover, ASCs were found to secret angiogenic cytokines in vitro and in vivo, including VEGF, HGF, and FGF2, which increase neovascularization and enhance wound healing in injured tissues. These results demonstrate that ASC therapy could accelerate wound healing through differentiation and vasculogenesis and might represent a novel therapeutic approach in cutaneous wounds.[33] Impaired wound healing is a challenge causing debilitating effects with tremendous suffering. Stem cell therapy has emerged as a novel therapeutic approach for various diseases including wound repair and tissue regeneration. [33] Several different types of stem cells have been studied in both preclinical and clinical settings such as bone marrow-derived stem cells, adiposederived stem cells (ASCs), circulating angiogenic cells (e.g., endothelial progenitor cells), human dermal fibroblasts, and keratinocytes for wound healing. Adipose tissue is an abundant source of
mesenchymal stem cells, which have shown an improved outcome in wound healing studies. [33] ASCs are pluripotent stem cells with the ability to differentiate into different lineages and to secrete paracrine factors initiating tissue regeneration process. The abundant supply of fat tissue, ease of isolation, extensive proliferative capacities ex vivo, and their ability to secrete proangiogenic growth factors make them an ideal cell type to use in therapies for the treatment of nonhealing wounds. In this review, the authors evaluated the pathogenesis of chronic wounds, the role of stem cells in wound healing, and the role of ASCs, their mechanism of action and their safety profile in wound repair and tissue regeneration. [34] Role of Mast Cells in Wounds, Trauma and Injury: Wound healing is a complex lytic process and reconstitution controlled by a series of cell signalling proteins. Mast cells (MCs) have been shown to play a significant role in the early inflammatory stage of wound healing and influence proliferation and skin tissue remodeling. [35] This study of MC’s and wound healing involved the use of cell studies and animal models through the use of mast cell inhibitors, promoters and mast cell deficient rodent strains. This review addressed wound healing in skin and the gastrointestinal tract and specifically identified data pertaining to the role of the mast cell in the process of cell breakdown, repair and regeneration. [35] MCs play a central role in early innate immune systemic responses after trauma and can induce inflammation after injury. They are the first-line but unstudied responders in trauma and are also contributors to the initial inflammatory response after hemorrhagic shock, trauma and tissue injury. [36] MCs have been also been shown to be involved in wound healing, electrosensitivity, cerebral ischemia and reperfusion injury, and burns.[37][38]..
Surgical Management: This article outlined the important role the surgeon plays in the management of chronic wounds . [39] Debridement and washout are required for grossly infected wounds and necrotizing soft tissue infections. Arterial, venous, and even lymphatic flows can be restored in select cases to enhance delivery of nutrients and removal of metabolic waste and promote wound healing. In cases where vital structures, such as bones, joints, tendons, and nerves, are exposed, vascularized tissue transfers are often required. [39] These tissue transfers can be local or remote, the latter of which necessitates anastomoses of arteries and veins. Pressure sores are managed by relieving pressure, treating acute trauma or infection, and using rotation fasciocutaneous flaps. The surgeon must always consider the possibility of osteomyelitis and retained foreign body as etiology for chronic wounds.[39]
Burns, Trauma and Injury: Severe burns and associated wounds can cause a pathological stress response.[36] Post traumatic stress can occur in burn patients and life threat perceptions are known to be a strong predictor for post traumatic stress disorders, and by acute intrusive symptoms in burn pain patients with associated injuries [40]. Burn wounds can lead to the large scars influencing patients' quality of life. This review of the literature examined a focus on recent data on postburn pathological scars, epidemiology and risk factors, which underlines the high prevalence and the long evolution, pointing to identification of this illness as a systemic inflammatory response, more frequent in women and in younger ages, regulated by local factors relevant in wound healing.[41]
In adult mammalian skin tissue injury frequently leads to scarring however, fetal mammalian skin heals with complete regeneration. Inflammatory reactions are factors thought to impair regeneration. In this animal study tolerant mice also showed fewer myofibroblasts and reduced scar area.[42] Furthermore, tolerant mice showed a pattern of extracellular matrix deposition similar to that observed in intact skin, plus characteristics of regeneration, as an increased deposition of fibronectin and tenascin-C. These observations suggested that the indirect effects of oral tolerance can alter the process of wound healing in skin and reduce scar formation. [42] Epidemiology and outcomes of pediatric burns was evaluated with data from January 1974 until August 2010. The age of the patient, cause of burn, total body surface area , burn depth , and patient outcomes were collected.[43] Demographics were compared with regional census data. Mortality was significantly correlated with inhalation injury, size of burn, and history of abuse. Over 35 years in North Texas, the median burn size and incidence of pediatric burn admissions decreased. and the, length of stay and mortality have also decreased. [43]. Trauma: Injury due to trauma can induce immune function changes, which can lead to both proinflammatory activation.Traumatic brain injury (TBI) is a major cause of mortality and morbidity worldwide. Studies have revealed that the pathogenesis of TBI involves upregulation of MMPs which are primarily responsible for the dynamic remodulation of the extracellular matrix (ECM). Thus, they are involved in several normal physiological processes, growth, development, and wound healing. During pathophysiological conditions MMPs proteolytically degrade various components of the ECM and tight junction (TJ) proteins of BBB and cause blood brain barrier disruption. In this review, the roles of MMPs in various
physiological/pathophysiological processes associated with neurological complications, with special emphasis on TBI were explored.[44] Severe trauma initiates inflammatory cascades and excessive cytokine production, which is one of the bases of the systemic inflammatory response syndrome and multiple-organ failure. Interleukin 6 (IL-6), an important cytokine is expressed by various cells after many stimuli and it underlies complex regulatory control mechanisms. Following major trauma, IL-6 release correlates with injury severity, complications, and mortality.[45] . Interleukin-10 (IL-10) can markedly inhibit lymphocyte and phagocytic functions, essential for an adequate immune response.[46] In this early study patients who died from injury or developed posttraumatic complications due to multiple organ dysfunction syndrome had elevated IL-10 levels in comparison with injured patients with an uneventful posttraumatic course. Thus, trauma causes an enhanced release of IL-10 dependent on the severity of injury. Because increased IL-10 levels are significantly related to posttraumatic complications, IL-10 may be involved in their pathogenesis.[46] A significant increase of both IL-6 and IL-10 concentrations was found over time in a reported study, with a significant correlation found between Injury Severity Score and the levels of both IL-6 and IL-10 at all sampling points. Serum concentrations of IL-6 and IL-10 were significantly higher in patients not surviving 30 days. The early systemic inflammatory response measured as IL-6 and IL-10 in serum is correlated with injury severity and 30-day mortality following trauma.[47] The innate immune system is an immunomonitor and has a very prominent role in organ failure after trauma. Polymorphonuclear phagocytes and monocytes are the main effector-
cells of the innate immune system that are involved in organ failure and are controlled by cytokines, chemokines, complement factors and specific tissue signals.[48] The impact of trauma on neutrophil function was evaluated by Hazeldine.[49] With traumainduced changes in neutrophil biology linked to the development of such post-traumatic complications as multiple organ failure and acute respiratory distress syndrome, an area of research within the field of trauma immunology that is gaining considerable interest is the manipulation of neutrophil function as a means by which to potentially improve patient outcome.[49] Enormous efforts to elucidate the mechanisms of the development of multiple organ failure following trauma have been done, but multiple organ failure following trauma is still a leading cause of late post-injury death and morbidity.[50] Excessive systemic inflammation following trauma participates in the development of multiple organ failure. The inflammatory response is a host-defense response; but this response can turns around to cause host deterioration depending on exo- and endogenic factors.[50] This review described the pathophysiological approach for multiple organ failure after trauma studied and also introduced the prospects of this issue for the future.[50] Many complex factors, such as genetics, physical agents, mediators in the development of organ failure both in sinusitis, stress, depression and trauma, lead to posttraumatic organ failure.[51. This review discussed chronic rhinosinusitis, sinusitis related to trauma, the innate and adaptive immunology, NF-kappa B related to inflammation, sepsis, complement, inflammation, reactive oxygen species, asthma pathogenesis, and asthma in the elderly, oxidative stress, depression, seasonal variation and vitamin D, cytokines, genetic susceptibility related to sepsis, hereditary angioedema related to trauma and stress.[51]
MCs are causative of neurologic disorders and evidence of decreased disease related to MC products. These include the systemic inflammation response syndrome, sepsis, cell signaling, complement activation, hemorrhagic shock, wound healing, cerebral ischemia and reperfusion injury, burns, and stroke injury.[52] The multiple roles of TH2 cells in maintaining and altering the balance between TH1 and TH2 responses are important mechanisms for tissue damage related to trauma. Understanding the neuroimmunology, stress response, could lead to contribute to novel treatments for immediate and late reactions.Treatment of disorders should include stress management and behavioral intervention to prevent trauma and stress-related immune imbalances.[52] Conclusion: This paper reviewed many area related to wounds, photobiomodulation, reactive oxygen species,
biofilms, neutrophils in wounds, other cells and growth factors in wounds, T cells in wounds, additional role of stem cell in wounds, mast cells in wounds, trauma and injury, surgical management, burns, trauma and injury, cytokines and trauma.
,
References [1]. Shaikh G, Cronstein B. Purinergic .Signaling pathways involving adenosine A2A and A2B receptors in wound healing and fibrosis.Signal 2016; Feb 4. [2]. De Jesus AM, Aghvami M, Sander EAA. Combined In Vitro Imaging and Multi-Scale Modeling System for Studying the Role of Cell Matrix Interactions in Cutaneous Wound Healing. PLoS One. 2016; Feb 3;11(2): [3] Yu T, Stockmann C, Healy DP et al..Optimal Amikacin Dosing Regimens for Pediatric Patients with Burn Wound Sepsis J Burn Care Res. 2014; Sep 2. [4]. Kuffler DP. Photobiomodulation in promoting wound healing: a review. Regen Med. 2016; Jan;11(1):107-22 [5] Khan I, Arany P. Biophysical approaches for oral wound healing: emphasis on photobiomodulation. Adv Wound Care (New Rochelle) 2015;4(12):724–737 [6]. Syed S, Zubair A, Frieri M.Immune response to nanomaterials: implications for medicine and literature review. Curr Allergy Asthma Rep. 2013; Feb;13(1):50-7 [7]. Madeo J, Zubair A, Marianne F. A review on the role of quinones in renal disorders. Springerplus. 2013; Dec;2(1):139. [8]. Parihar A, Parihar MS, Milner S, et al. Oxidative stress and anti-oxidative mobilization in burn injury. Burns. 2008; Feb;34(1):6-17. [9].Percival SL, Francolini I, Donelli G. Low-level laser therapy as an antimicrobial and antibiofilm technology and its relevance to wound healing. Future Microbiol. 2015;10(2):255– 272. [10] Madeo J, Frieri M. Bacterial biofilms and chronic rhinosinusitis. Allergy Asthma Proc. 2013; Jul-Aug;34(4):335-41
[11]. Kilty SJ, Desrosiers MY. Are biofilms the answer in the pathophysiology and treatment of chronic rhinosinusitis? Immunol Allergy Clin North Am 2009; 29:645– 656. [12]. Hoiby N, Ciofu O, Johansen HK, et al. The clinical impact of bacterial biofilms. Int J Oral Sci 2011; 3:55– 65. [13]. Rajpaul K. Br J Biofilm in wound care. Community Nurs. 2015; Mar;Suppl Wound Care:S6, S8, S10-1. [14] Seth AK, Zhong A, Nguyen KT et al. Impact of a novel, antimicrobial dressing on in vivo, Pseudomonas aeruginosa wound biofilm: quantitative comparative analysis using a rabbit ear model. Wound Repair Regen. 2014 Nov-Dec;22(6):712-9. [15]. James GA, Zhao AG, Usui M et al. Microsensor and transcriptomic signatures of oxygen depletion in biofilms associated with chronic wounds. Wound Repair Regen. 2016; Jan 7 [16]. Fathabadie FF., Bayat M., Amini A.et al. Effects of pulsed infra-red low level-laser irradiation on mast cells number and degranulation in open skin wound healing of healthy and streptozotocin-induced diabetic rats. J Cosmet Laser Ther 2013;15:294–304. [17].AlGhamdi KM., Kumar A., Moussa NA. Low-level laser therapy: a useful technique for enhancing the proliferation of various cultured cells. Lasers Med Sci 2012;27:237–249. [18]. Pallotta RC., Bjordal JM., Frigo L, et al. Infrared (810-nm) low-level laser therapy on rat experimental knee inflammation. Lasers Med Sci 2012;27:71–78. [19]. Oliveira MC., Jr., Greiffo FR., Rigonato-Oliveira NC, et al. Low level laser therapy reduces acute lung inflammation in a model of pulmonary and extrapulmonary LPS-induced ARDS. J Photochem Photobiol B 2014;134:57–63. [20].Asghari S, Logsetty S, Liu S Imparting commercial antimicrobial dressings with lowadherence to burn wounds.Burns. 2016; Feb 1.
[21] Seo BF, Jung SN. The Immunomodulatory Effects of Mesenchymal Stem Cells in Prevention or Treatment of Excessive Scars. Stem Cells Int. 2016;2016:6937976. [22].Dyer DP, Thomson,JM Hermant A et al., “TSG-6 inhibits neutrophil migration via direct interaction with the chemokinen CXCL8, Journal of Immunology, 2014;. vol. 192, no. 5, pp. 2177–2185. [23] Thomsen K, Trøstrup H, Christophersen L et al.The phagocytic fitness of Leucopatches may impact the healing of chronic wounds. Clin Exp Immunol. 2016; Feb 27 [24] Gauglitz, GG Korting,HC PavicicT et al. Hypertrophic scarring and keloids: pathomechanisms and current and emerging treatment strategies,” Molecular Medicine, 2011; vol. 17, no. 1-2, pp. 113–124. [25] Gurtner GC, Werner, S Barrandon, Y et al., “Wound repair and regeneration,” Nature, 2008;vol. 453, no. 7193, pp. 314–321. [26]. Placik OJ , Lewis Jr.VL. Immunologic associations of keloids. Surgery, Gynecology & Obstetrics, 1992; vol. 175, no. 2, pp. 185–193. [27].Walmsley GG, Maan, ZN, Wong VW et al., Scarless wound healing: chasing the holy grail, Plastic and Reconstructive Surgery 2015;, vol. 135, no. 3, pp. 907–917. [28]. Smith RE, Strieter RM, . Phan SH et al, TNF and IL-6 mediate MIP-1ߙ expression in bleomycin-induced lung injury. Journal of Leukocyte Biology.1998;, vol. 64, no. 4, pp. 528–536, [29]. Satish L . Kathju S, Cellular and molecular characteristics of scarless versus fibrotic wound healing, Dermatology Research and Practice 2010; vol. Article ID 790234, 11 pages.. [30]. Nosbaum A, Prevel N, Truong HA et al. Cutting Edge: Regulatory T Cells Facilitate Cutaneous Wound Healing. J Immunol. 2016; Jan 29.
[31] Seo BF, Jung SN The Immunomodulatory Effects of Mesenchymal Stem Cells in Prevention or Treatment of Excessive Scars. Stem Cells Int. 2016;2016:6937976. [32]. Jeong JH. Adipose stem cells and skin repair. Curr Stem Cell Res Ther. 2010; Jun;5(2):137-40. [33]. Nie C, Yang D, Xu J et al. Locally administered adipose-derived stem cells accelerate wound healing through differentiation and vasculogenesis Cell Transplant. 2011;20(2):205-16. [34]. Hassan WU, Greiser U, Wang W.Role of adipose-derived stem cells in wound healing. Wound Repair Regen. 2014; May-Jun;22(3):313-25. [35] Kennelly R, Conneely JB, Bouchier-Hayes D et al.,Mast cells in tissue healing: from skin to the gastrointestinal tract. Curr Pharm Des. 2011; Nov;17(34):3772-5 [36].Cai C, Gill R, Eum HA, et al. Complement factor 3 deficiency attenuates hemorrhagic shock-related hepatic injury and systemic inflammatory response syndrome. Am J Physiol Regul Integr Comp Physiol. 2010;299:R1175eR1182. [37]. Shiota N, Nishikori Y, Kakizoe E, et al. Pathophysiological role of skin mast cells in wound healing after scald injury: study with mast cell deficient W/ W(V) mice. Int Arch Allergy Immunol. 2010;151:80e88 [38] Younan G, Suber F, Xing W, et al. The inflammatory response after an epidermal burn depends on the activities of mouse mast cell proteases 4 and 5. J Immunol. 2010;185:7681e7690). .[39]. Johnston BR, Ha AY, Kwan D Surgical Management of Chronic Wounds. R I Med J (2013). 2016; Feb 1;99(2):28-31.
[40]. Giannoni-Pastor A, Eiroa-Orosa FJ, Fidel Kinori SG et al. Prevalence and Predictors of Posttraumatic Stress Symptomatology Among Burn Survivors: A Systematic Review and MetaAnalysis.J Burn Care Res. 2016; Jan-Feb;37(1):e79-89) [41].Stella M, Castagnoli C, Gangemi EN Postburn scars: an update. Int J Low Extrem Wounds. 2008; Sep;7(3):176-81. [42] Costa RA, Ruiz-de-Souza V, Azevedo GM Jr, et al Indirect effects of oral tolerance improve wound healing in skin.Wound Repair Regen. 2011; Jul-Aug;19(4):487-97 [43].Saeman MR,,Hodgman EI, Burris A et al. Epidemiology and outcomes of pediatric burns over 35 years at Parkland Hospital. Burns. 2015; Nov 21. [44]. Abdul-Muneer PM, Pfister BJ, Haorah J et al. Role of Matrix Metalloproteinases in the Pathogenesis of Traumatic Brain Injury Mol Neurobiol. 2015; Nov 5. [45].Gebhard F, Pfetsch H, Steinbach G, et al. Interleukin 6 an early marker of injury severity following major trauma in humans? Arch Surg. 2000;135: 291e295 [46].Neidhardt R, Keel M, Steckholzer U, et al. Relationship of interleukin-10 plasma levels to severity of injury and clinical outcome in injured patients.J Trauma. 1997;42:863e870. [47].Stensballe J, Christiansen M, Tønnesen E, et al. The early IL-6 and IL-10 response in trauma is correlated with injury severity and mortality. Acta Anaesthesiol Scand. 2009;53:515e521. [48].Hietbrink F, Koenderman L, Rijkers GT, Leenen L.l. Trauma: the role of the innate immune system. World Journal of Emergency Surgery. 2006.. [49] Hazeldine J, Hampson P, Lord JM The impact of trauma on neutrophil function Injury 2014;. Dec;45(12):1824-33
[50]. Tsukamoto T, Chanthaphavong RS, Pape HC Current theories on the pathophysiology of multiple organ failure after trauma. Injury 2010;.Jan;41(1):21-6.. [51] Frieri M, Kumar K, Boutin A.Review: Immunology of sinusitis, trauma, asthma, and sepsis. Allergy Rhinol (Providence). 2015; Jan;6(3):205-14. [52].Frieri M, Kumar K, Boutin A.Role of mast cells in trauma and neuroinflammation in allergy immunology.Ann Allergy Asthma Immunol. 2015; Sep;115(3):172-7. .
S2213-9095(16)30004-0 http://dx.doi.org/doi:10.1016/j.wndm.2016.02.004 WNDM 72
To appear in: Received date: Accepted date:
17-2-2016 21-2-2016
Please cite this article as: Marianne Frieri, Krishan Kumar, Anthony Boutin, Wounds, Burns, Trauma, and Injury, Wound Medicine http://dx.doi.org/10.1016/j.wndm.2016.02.004 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Wounds, Burns, Trauma, and Injury
Marianne Frieri, M.D., Ph.D1, Krishan Kumar, M.D2, Anthony Boutin, M.D3. Division of Allergy Immunology1, Department of Medicine,1 Division of Pediatric2 and Adult Emergency Medicine3, Department of Emergency Medicine 2,3 Nassau University Medical Center 2201 Hempstead Turnpike, East Meadow, NY 11554 Krishan Kumar, M.D,,telephone :516-567-9855, fax: 516-572-54 65 .email: [email protected] Anthony Boutin, M.D.telephone:516-572-6175, fax: 516-572-5465 email:[email protected] Address corrrespondence to Marianne Frieri, M.D., Ph.D Nassau University Medical Center, Department of Medicine 2201 Hempstead Turnpike, East Meadow, New York, 11554 Telephone:516-572-6501,fax:516-572 5609,email:[email protected]
Abstract: The purpose of this review paper is to discuss many areas related to wounds, photobiomodulation, reactive oxygen species, biofilms, neutrophils in wounds, other cells and growth factors in wounds, T cells in wounds, additional role of stem cell in wounds, mast cells in wounds, trauma and injury, surgical management, burns, trauma and injury, cytokines and trauma
Key words: wounds, burns, photobiomodulation, biofilms, trauma, injury
Introduction Wounds: In wound healing, fibroblasts collagen and matrix deposition are important for healing, however this material can contribute to remodeling of organs with substantial morbidity and mortality.[1] Certain receptors can lead to fibroblast activation, collagen synthesis and adenosines, a small molecule extracellularly generated from adenine nucleotides from direct stimulation, hypoxia, or injury can act via a family of classical seven-pass G protein-coupled protein receptors as discussed in a recent article.[1] Signaling pathways are involved with adenosine receptors and in wound healing as described in this recent article [1] Adenosine and its receptors play important roles in both production of matrix and neovascularization, critical areas for wound healing and tissue repair. These receptors are A2A and A2B, with generation of cAMP and activation of downstream targets such as protein kinase A and exchange protein activated by cAMP or EPAC, a family of guanine nucleotide exchange factors can cause activation of fibroblast and also collagen synthesis.[1]. Adenosine signaling contributes to fibrosis and may have opposite effects in a variety of different organs. Thus, drug development that selectively target these receptors and signaling pathways will disrupt fibrosis pathogenesis and slow or arrest the progression of important underlying disorders.. In a recent article these authors reported on the development of an image-based multi-scale mechanical model that predicts the short-term structural reorganization of a fibrin gel by fibroblasts.[2] Regional differences in short-term structural remodeling and cell migration were observed for two gel boundary conditions. A pilot experiment indicated that these small differences in the short-term remodeling of the fibrin gel translated into substantial differences in long-term remodeling for collagen production.[2] The multi-scale models predicted some
regional differences in remodeling and qualitatively similar reorganization patterns for the two boundary conditions. However, other aspects of the model, magnitudes and rates of deformation of gel did not match the experiments. These discrepancies between model and experiment can be important for challenging model assumptions and devising new experiments enhancing the understanding of how this multi-scale system functions. Thus, these efforts can improve the predictions of remodeling, dermal wound healing and reduction of patient scarring. These models could be used to recommend patient-specific mechanical-based treatment dependent on s wound geometry, location, age, and health.[2] A study aimed to develop optimal amikacin dosing for the empirical treatment of Gram-negative bacterial sepsis in pediatric patients with burn injuries.[3] Optimal amikacin dosing regimens for the empirical treatment of Gram-negative bacterial sepsis in pediatric patients with burn injuries were developed. [3] The authors stated amikacin pharmacokinetics are altered in patients with burn injuries, including a significant increase in clearance and the volume of distribution in simulations, increased doses (≥25 mg/kg) led to improved PD target attainment rates. Further clinical evaluation of this proposed dosing regimen is warranted to assess clinical and microbiological outcomes in pediatric patients with burn wound sepsis. [3]
Photobiomodulation: Treatments for many wounds can be recalcitrant and an area of photobiomodulation involves inducing wound healing by illuminating wounds with light emitting diodes or lasers. [4] Photobiomodulation is used on different animal models, in vitro studies, and clinically. Wound healing is induced by many different wavelengths and powers with no optimal set of parameters. [4] Simultaneous multiple wavelength illumination according to data suggest it is more
efficacious than single wavelengths, and the optimal single and multiple wavelengths must be better defined to induce more reliable and extensive healing of different wound types. These authors focused on studies in which specific wavelengths could induce wound healing and on their mechanisms. [4] Reactive Oxygen Species: Photobiomodulation is defined as a nonthermal process involving endogenous chromophores that are able to elicit photophysical and photochemical events at various scales, resulting in beneficial photobiological responses. There appears to be enough anecdotal scientific literature for the use of light in wound care from sterilization, desiccation, promotion of healing and effective treatment for a number of conditions, including inflammation.[5] In terms of the mechanism of photobiomodulation, interaction of light and biological tissues can lead to generation of transient and extremely reactive chemical intermediates, or reactive oxygen species (ROS), in both extracellular and intracellular compartments. [5] The different materials, sizes, shapes, and structures have different responses. This paper investigated the successful treatments made with nanoparticles and some general health effects. A review of the literature revealed an inflammatory response and an increased production of ROS, common immune responses to nanomaterial use. The mechanisms by which the inflammatory response and ROS production was discussed.[6] Quinones are electron proton carriers that play a primary role in the aerobic metabolism of virtually every cell. Quinones undergo highly regulated redox reactions in the mitochondria, Golgi apparatus, plasma membrane and endoplasmic reticulum. Important consequences of these electron transfer reactions are the production of and protection against ROS. Quinones have been
extensively studied for both their cytotoxic as well as cellular protective properties and they have been particularly useful in rational drug design. [7] A severe burn is associated with release of inflammatory mediators which ultimately cause local and distant pathophysiological effects. [8] Mediators including ROS and Reactive Nitrogen Species (RNS) are increased in affected tissue, which are implicated in pathophysiological events observed in burn patients.[8] However following a burn, there is an enormous production of ROS which is harmful and implicated in inflammation, SIRS, immunosuppression, infection and sepsis, tissue damage and multiple organ failure. Thus, clinical response to burn is dependent on the balance between production of free radicals and its detoxification. Supplementation of antioxidants in human and animal models has proven benefit in decreasing distant organ failure suggesting a cause and effect relationship. Oxidative damage is one of the mechanisms responsible for the local and distant pathophysiological events observed after burn, and therefore anti-oxidant therapy might be beneficial in minimizing injury in burned patients. [8] Biofilms A beneficial effect of low-level laser therapy in promoting wound healing in both animal and human studies has been demonstrated.[9] This recent review identified literature reporting on low-level laser therapy alone, without photodynamic agents, as an antimicrobial/antibiofilm technology and determined its effects on wound healing.[9] The authors stated efforts need to be addressed to standardize phototherapy and develop suitable in vitro and in vivo biofilm models to test low-level laser therapy efficacy in promoting biofilm eradication and wound healing.[9] Biofilms due to Staphylococcus aureus and exotoxins that act as superantigens have been implicated to play an important pathological role in the incidence, maintenance, and ongoing burden of chronic rhinosinusitis as well as in wounds. [10] A better understanding of the
interplay between bacterial factors, host factors, and the environment will facilitate better management. This literature review focused on these factors and highlights current research in this field that could relate to wounds.[10] Biofilm growth is associated with an increased in mutations. Infection in the form of biofilm may have an important role in the maintenance of the recalcitrant inflammation for not only chronic sinusitis but could relate to wound healing, also a common chronic condition.[11].Bacterial biofilms are resistant to antibiotics, disinfectants, phagocytosis and other components of the innate and adaptive inflammatory defense system.[12] Antibiotic resistance is enhanced by the ability of resident bacteria cells to share genetic material within the biofilm structure, thus facilitating the persistence of antibiotic-resistant genes.[12] These authors stated biofilms can be prevented by antibiotic prophylaxis or early aggressive antibiotic therapy as in wounds and treated by chronic suppressive antibiotic therapy. Promising strategies may include the use of compounds which can dissolve the biofilm matrix and increases biofilm susceptibility to antibiotics and phagocytosis.[12] Biofilms can affect chronic wound healing due to the production of destructive enzymes and toxins that can lead to a chronic inflammatory state. They also can be polymicrobial and can result in delayed wound healing with chronic wound infection resistant to antibiotics. The authors of this recent article suggest that biofilms are a major player in the chronicity of wounds and they are a complex concept to diagnose and management.[13] An animal study was evaluated on the impact of a novel, antimicrobial dressing on Pseudomonas aeruginosa biofilm-infected wounds.[14] This dressing consistently decreased P. aeruginosa bacterial counts and improved wound healing. The authors stated this study was the first quantifiable and consistent in vivo evidence of a topical antimicrobial dressing's impact against
established wound biofilm and the development of clinically applicable therapies against biofilm related to this area s is critical to improving chronic wound care.[14] This recent animal study demonstrated that oxygen consumption by biofilms and by the responding leukocytes, may impede wound healing by depleting the oxygen required for healing. These results supported the hypothesis that bacterial biofilms in chronic wounds lead to chronicity by contributing to maintenance of localized low oxygen tensions, through their metabolic activities and their recruitment of cells that consume oxygen for the processes related host defensive.[15] Photobiomodulation has been noted to promote platelet aggregation and activation in the inflammatory phase, it is also known to promote proliferation and degranulation of mast cells [16] In the proliferative phase, photobiomodulation promotes proliferation of cells such as fibroblasts, keratinocytes, osteoblasts, and chondrocytes and induces matrix synthesis.[17] The antiinflammatory effects of photobiomodulation therapy are direct effects on both pro- and antiinflammatory factors, such as IL-1, IL-8, Cox1, and Cox 2. others. [18][19] The objective of this study was to decrease adherence of wounds of commercial silver based wound dressings using a non-adherent layer.[20] This non-adherent layer was thought to lower the dressing's adherence to burn wounds with no compromise on antimicrobial activity or increase in the cytotoxicity. A grafted polyacrylamide served as the non-adherent layer and dressing adherence was measured with an other published in vitro gelatin model. The dressings were challenged with two clinically retrieved bacterial strains of Methicillin-resistant Staphylococcus aureus and multidrug resistant Pseudomonas aeruginosa with both a disk diffusion test, and antibacterial test suspension.[20] It was noted by the authors that fibroblast
survival was improved by the polyacrylamide grafting and that the polyacrylamide as a nonadherent layer significantly decreased the adherence of these two commercial antimicrobial dressings in an in vitro gelatin model while preserving their antimicrobial efficacy, thus reducing cytotoxicity.[20] Excessive scars, such as keloids and hypertrophic scars result from aberrations in physiologic wound healing and an exaggerated inflammatory process is one of the main pathophysiological issues.[21] Scars can lead to pain, pruritis, limit joint mobility, and cause a range of cosmetic deformities affecting the patient's quality of life and extensive research has been done on hypertrophic scar and keloid formation resulting in the many treatments and prevention methods. [21] Mesenchymal stem cells, among their multifunctional roles, are known regulators of inflammation and are a major candidate for cell therapy to treat or prevent excessive scars. This paper reviewed extensively research examining the mechanism and potential of stem cell therapy in the treatment of excessive scars. [21] Neutrophils in Wounds: Neutrophils are important inflammatory cells. They arrive at the wound through chemotaxis, traversing postcapillary venules to degrade pathogens with granules within phagolysosomes, and lead to cell death or apoptosis.[22] IL-10 secreted by mesenchymal stem cells inhibit neutrophil invasion into the wound. Mesenchymal stem cells secrete TNF-stimulated gene/protein-6 (TSG6),which interacts with protein ligands inhibiting rolling and neutrophil transendothelial migration. Dyer noted that TSG-6 interacts with the glycosaminoglycan binding site of CXCL8 (IL-8), a chemokine produced by macrophages and transported to the surface of the endothelium, impairing neutrophil adhesion and migration.[22]
Chronic non-healing wounds are a significant bothersome area to patients and can result in severe complications.[23] Handling of chronic, non-healing wounds can be discouraging due to lack of improvement, and a recent explanation can be involvement of biofilm infections in the pathogenesis of non-healing wounds. Autologous leucopatches are a new, adjunctive therapeutic option, with promising clinical effects and a major contribution is believed to result from the release of stimulating growth factors from activated thrombocytes within the leucopatch.[23] Leucopatches contain substantial number of leucocytes and the aim of the present study was to investigate the activity of the polymorphonuclear neutrophils (PMNs) within the leucopatch. The authors showed significant PMN respiratory with active phagocytosis and killing of Pseudomonas aeruginosa by the leucopatch. Bacterial induced migration of PMNs from the leucopatch, and uptake of P. aeruginosa by PMNs within the leucopatch developed. This study substantiated that the beneficial clinical effect in chronic wounds by leucopatches is attributed to the activity of the PMNs within the leucopatch.[23] Although the definitive process underlying such scar formation is yet to be elucidated, the upregulated, exaggerated inflammatory response has been found to be a critical step in achieving excessive scars.[24][25] Other Cells and Growth Factors Involved in Wounds: Normal physiologic wound healing in adults undergoes three overlapping phases: inflammation, proliferation, and remodeling.[26] After injury, platelet degranulation and activation of complement and coagulation cascades result in formation of a fibrin clot at the site of injury. This structure provides hemostasis and functions as the seat of wound chemotaxis. This temporary extracellular matrix (ECM) stimulates recruitment of inflammatory cells such as neutrophils, macrophages, epithelial cells, mast cells, endothelial cells, and fibroblasts, which in turn produce proinflammatory mediators including macrophage inflammatory protein- 1alpha
(MIP-1ߙ), monocyte chemotactic protein-1 (MCP- 1), RANTES, interleukin-1beta (IL-1ߚ), and interleukin-6.[27][28] Inflammatory cells deliver a wide range of growth factors, such as transforming growth factorbeta 1 (TGF-ߚ1), transforming growth factor-alpha (TGF-ߙ), basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF), and platelet derived growth factor (PDGF) . [29] T Cells in Wounds: T regulatory cells or Tregs, produce specific effector cytokines under unique transcriptional regulation. Burn injury can induce global changes to the systemic immune response, including suppressed immune function and increased susceptibility to infection and, burn trauma is associated with remote organ injury. After postburn injury, a decreased Th17/Th1 ratio could contribute to increased susceptibility to extracellular pathogens. In this article, the authors showed that Tregs facilitate cutaneous wound healing. Tregs that accumulate in the skin early after wounding, and specific ablation of these cells has resulted in delayed wound re-epithelialization and kinetics of wound closure.[30] Tregs in wounded skin also attenuated IFN-γ production and proinflammatory macrophage accumulation. Tregs also induce expression of the epidermal growth factor receptor (EGFR) upon wounding. However lineage-specific deletion of EGFR in Tregs resulted in reduced Treg accumulation and activation in wounded skin, delayed wound closure, and increased proinflammatory macrophage accumulation. The results of this study revealed a novel role for Tregs in facilitating skin wound repair and suggest the use the EGFR pathway to mediate these effects.[30]
Additional Role of Stem Cell in Wounds: Mesenchymal stem cells, among their multifunctional roles, are known regulators of inflammation and have been receiving attention as a major candidate for cell therapy to treat or prevent excessive scars. This paper extensively reviewed the body of research examining the mechanism and potential of stem cell therapy in the treatment of excessive scars.[31] With the discovery of adipose stem cells (ASCs), 40 years after the identification of bone marrow stem cells, a new era of active stem cell therapy has opened. [32] ASCs are already clinically applied in many other purposes such as cell-enriched lipotransfer, wound healing, skin rejuvenation, scar remodeling and skin tissue engineering. Researches have disclosed some of their unique functions as mesenchymal stem cells. There have been increasing numbers of scientific reports on the therapeutic effect of ASCs on skin repair, scar remodeling and rejuvenation. Wound healing and scar remodeling are complex, multi-cellular processes that involve coordinated efforts of many cell types and various cytokines reports showed ASCs as a powerful source of skin regeneration because of their capability to provide not only cellular elements, but also numerous cytokines. Currently, other attractive functions of ASCs in the recovery of extrinsic aging and radiation damage are under active investigation. It seems that autologous ASCs have great promise for applications in repair of skin, rejuvenation of aging skin and aging-related skin lesions. This review focused on the specific roles of ASCs in skin tissue, especially related with wound healing, radiation injury, scar remodeling, skin rejuvenation and skin engineering.[32] Recently, stem cell therapy has emerged as a new approach to accelerate wound healing. [33] Adipose-derived stem cells (ASCs) hold great promise for wound healing, because they are multipotential stem cells capable of differentiation into various cell lineages and secretion of
angiogenic growth factors. The aim of this study was to evaluate the benefit of ASCs on wound healing and then investigate the probable mechanisms.[33] ASCs characterized by flow cytometry were successfully isolated and cultured. An excisional wound healing model in rat was used to determine the effects of locally administered ASCs. The gross and histological results showed that ASCs significantly accelerated wound closure in normal and diabetic rat, including increased epithelialization and granulation tissue deposition.The authors applied GFPlabeled ASCs on wounds to determine whether ASCs could differentiate along multiple lineages of tissue regeneration in the specific microenvironment. Immunofluorescent analysis indicated that GFP-expressing ASCs were costained with pan-cytokeratin and CD31, indicating spontaneous site-specific differentiation into epithelial and endothelial lineages. These data suggested that ASCs not only contribute to cutaneous regeneration, but also participate in new vessels formation. Moreover, ASCs were found to secret angiogenic cytokines in vitro and in vivo, including VEGF, HGF, and FGF2, which increase neovascularization and enhance wound healing in injured tissues. These results demonstrate that ASC therapy could accelerate wound healing through differentiation and vasculogenesis and might represent a novel therapeutic approach in cutaneous wounds.[33] Impaired wound healing is a challenge causing debilitating effects with tremendous suffering. Stem cell therapy has emerged as a novel therapeutic approach for various diseases including wound repair and tissue regeneration. [33] Several different types of stem cells have been studied in both preclinical and clinical settings such as bone marrow-derived stem cells, adiposederived stem cells (ASCs), circulating angiogenic cells (e.g., endothelial progenitor cells), human dermal fibroblasts, and keratinocytes for wound healing. Adipose tissue is an abundant source of
mesenchymal stem cells, which have shown an improved outcome in wound healing studies. [33] ASCs are pluripotent stem cells with the ability to differentiate into different lineages and to secrete paracrine factors initiating tissue regeneration process. The abundant supply of fat tissue, ease of isolation, extensive proliferative capacities ex vivo, and their ability to secrete proangiogenic growth factors make them an ideal cell type to use in therapies for the treatment of nonhealing wounds. In this review, the authors evaluated the pathogenesis of chronic wounds, the role of stem cells in wound healing, and the role of ASCs, their mechanism of action and their safety profile in wound repair and tissue regeneration. [34] Role of Mast Cells in Wounds, Trauma and Injury: Wound healing is a complex lytic process and reconstitution controlled by a series of cell signalling proteins. Mast cells (MCs) have been shown to play a significant role in the early inflammatory stage of wound healing and influence proliferation and skin tissue remodeling. [35] This study of MC’s and wound healing involved the use of cell studies and animal models through the use of mast cell inhibitors, promoters and mast cell deficient rodent strains. This review addressed wound healing in skin and the gastrointestinal tract and specifically identified data pertaining to the role of the mast cell in the process of cell breakdown, repair and regeneration. [35] MCs play a central role in early innate immune systemic responses after trauma and can induce inflammation after injury. They are the first-line but unstudied responders in trauma and are also contributors to the initial inflammatory response after hemorrhagic shock, trauma and tissue injury. [36] MCs have been also been shown to be involved in wound healing, electrosensitivity, cerebral ischemia and reperfusion injury, and burns.[37][38]..
Surgical Management: This article outlined the important role the surgeon plays in the management of chronic wounds . [39] Debridement and washout are required for grossly infected wounds and necrotizing soft tissue infections. Arterial, venous, and even lymphatic flows can be restored in select cases to enhance delivery of nutrients and removal of metabolic waste and promote wound healing. In cases where vital structures, such as bones, joints, tendons, and nerves, are exposed, vascularized tissue transfers are often required. [39] These tissue transfers can be local or remote, the latter of which necessitates anastomoses of arteries and veins. Pressure sores are managed by relieving pressure, treating acute trauma or infection, and using rotation fasciocutaneous flaps. The surgeon must always consider the possibility of osteomyelitis and retained foreign body as etiology for chronic wounds.[39]
Burns, Trauma and Injury: Severe burns and associated wounds can cause a pathological stress response.[36] Post traumatic stress can occur in burn patients and life threat perceptions are known to be a strong predictor for post traumatic stress disorders, and by acute intrusive symptoms in burn pain patients with associated injuries [40]. Burn wounds can lead to the large scars influencing patients' quality of life. This review of the literature examined a focus on recent data on postburn pathological scars, epidemiology and risk factors, which underlines the high prevalence and the long evolution, pointing to identification of this illness as a systemic inflammatory response, more frequent in women and in younger ages, regulated by local factors relevant in wound healing.[41]
In adult mammalian skin tissue injury frequently leads to scarring however, fetal mammalian skin heals with complete regeneration. Inflammatory reactions are factors thought to impair regeneration. In this animal study tolerant mice also showed fewer myofibroblasts and reduced scar area.[42] Furthermore, tolerant mice showed a pattern of extracellular matrix deposition similar to that observed in intact skin, plus characteristics of regeneration, as an increased deposition of fibronectin and tenascin-C. These observations suggested that the indirect effects of oral tolerance can alter the process of wound healing in skin and reduce scar formation. [42] Epidemiology and outcomes of pediatric burns was evaluated with data from January 1974 until August 2010. The age of the patient, cause of burn, total body surface area , burn depth , and patient outcomes were collected.[43] Demographics were compared with regional census data. Mortality was significantly correlated with inhalation injury, size of burn, and history of abuse. Over 35 years in North Texas, the median burn size and incidence of pediatric burn admissions decreased. and the, length of stay and mortality have also decreased. [43]. Trauma: Injury due to trauma can induce immune function changes, which can lead to both proinflammatory activation.Traumatic brain injury (TBI) is a major cause of mortality and morbidity worldwide. Studies have revealed that the pathogenesis of TBI involves upregulation of MMPs which are primarily responsible for the dynamic remodulation of the extracellular matrix (ECM). Thus, they are involved in several normal physiological processes, growth, development, and wound healing. During pathophysiological conditions MMPs proteolytically degrade various components of the ECM and tight junction (TJ) proteins of BBB and cause blood brain barrier disruption. In this review, the roles of MMPs in various
physiological/pathophysiological processes associated with neurological complications, with special emphasis on TBI were explored.[44] Severe trauma initiates inflammatory cascades and excessive cytokine production, which is one of the bases of the systemic inflammatory response syndrome and multiple-organ failure. Interleukin 6 (IL-6), an important cytokine is expressed by various cells after many stimuli and it underlies complex regulatory control mechanisms. Following major trauma, IL-6 release correlates with injury severity, complications, and mortality.[45] . Interleukin-10 (IL-10) can markedly inhibit lymphocyte and phagocytic functions, essential for an adequate immune response.[46] In this early study patients who died from injury or developed posttraumatic complications due to multiple organ dysfunction syndrome had elevated IL-10 levels in comparison with injured patients with an uneventful posttraumatic course. Thus, trauma causes an enhanced release of IL-10 dependent on the severity of injury. Because increased IL-10 levels are significantly related to posttraumatic complications, IL-10 may be involved in their pathogenesis.[46] A significant increase of both IL-6 and IL-10 concentrations was found over time in a reported study, with a significant correlation found between Injury Severity Score and the levels of both IL-6 and IL-10 at all sampling points. Serum concentrations of IL-6 and IL-10 were significantly higher in patients not surviving 30 days. The early systemic inflammatory response measured as IL-6 and IL-10 in serum is correlated with injury severity and 30-day mortality following trauma.[47] The innate immune system is an immunomonitor and has a very prominent role in organ failure after trauma. Polymorphonuclear phagocytes and monocytes are the main effector-
cells of the innate immune system that are involved in organ failure and are controlled by cytokines, chemokines, complement factors and specific tissue signals.[48] The impact of trauma on neutrophil function was evaluated by Hazeldine.[49] With traumainduced changes in neutrophil biology linked to the development of such post-traumatic complications as multiple organ failure and acute respiratory distress syndrome, an area of research within the field of trauma immunology that is gaining considerable interest is the manipulation of neutrophil function as a means by which to potentially improve patient outcome.[49] Enormous efforts to elucidate the mechanisms of the development of multiple organ failure following trauma have been done, but multiple organ failure following trauma is still a leading cause of late post-injury death and morbidity.[50] Excessive systemic inflammation following trauma participates in the development of multiple organ failure. The inflammatory response is a host-defense response; but this response can turns around to cause host deterioration depending on exo- and endogenic factors.[50] This review described the pathophysiological approach for multiple organ failure after trauma studied and also introduced the prospects of this issue for the future.[50] Many complex factors, such as genetics, physical agents, mediators in the development of organ failure both in sinusitis, stress, depression and trauma, lead to posttraumatic organ failure.[51. This review discussed chronic rhinosinusitis, sinusitis related to trauma, the innate and adaptive immunology, NF-kappa B related to inflammation, sepsis, complement, inflammation, reactive oxygen species, asthma pathogenesis, and asthma in the elderly, oxidative stress, depression, seasonal variation and vitamin D, cytokines, genetic susceptibility related to sepsis, hereditary angioedema related to trauma and stress.[51]
MCs are causative of neurologic disorders and evidence of decreased disease related to MC products. These include the systemic inflammation response syndrome, sepsis, cell signaling, complement activation, hemorrhagic shock, wound healing, cerebral ischemia and reperfusion injury, burns, and stroke injury.[52] The multiple roles of TH2 cells in maintaining and altering the balance between TH1 and TH2 responses are important mechanisms for tissue damage related to trauma. Understanding the neuroimmunology, stress response, could lead to contribute to novel treatments for immediate and late reactions.Treatment of disorders should include stress management and behavioral intervention to prevent trauma and stress-related immune imbalances.[52] Conclusion: This paper reviewed many area related to wounds, photobiomodulation, reactive oxygen species,
biofilms, neutrophils in wounds, other cells and growth factors in wounds, T cells in wounds, additional role of stem cell in wounds, mast cells in wounds, trauma and injury, surgical management, burns, trauma and injury, cytokines and trauma.
,
References [1]. Shaikh G, Cronstein B. Purinergic .Signaling pathways involving adenosine A2A and A2B receptors in wound healing and fibrosis.Signal 2016; Feb 4. [2]. De Jesus AM, Aghvami M, Sander EAA. Combined In Vitro Imaging and Multi-Scale Modeling System for Studying the Role of Cell Matrix Interactions in Cutaneous Wound Healing. PLoS One. 2016; Feb 3;11(2): [3] Yu T, Stockmann C, Healy DP et al..Optimal Amikacin Dosing Regimens for Pediatric Patients with Burn Wound Sepsis J Burn Care Res. 2014; Sep 2. [4]. Kuffler DP. Photobiomodulation in promoting wound healing: a review. Regen Med. 2016; Jan;11(1):107-22 [5] Khan I, Arany P. Biophysical approaches for oral wound healing: emphasis on photobiomodulation. Adv Wound Care (New Rochelle) 2015;4(12):724–737 [6]. Syed S, Zubair A, Frieri M.Immune response to nanomaterials: implications for medicine and literature review. Curr Allergy Asthma Rep. 2013; Feb;13(1):50-7 [7]. Madeo J, Zubair A, Marianne F. A review on the role of quinones in renal disorders. Springerplus. 2013; Dec;2(1):139. [8]. Parihar A, Parihar MS, Milner S, et al. Oxidative stress and anti-oxidative mobilization in burn injury. Burns. 2008; Feb;34(1):6-17. [9].Percival SL, Francolini I, Donelli G. Low-level laser therapy as an antimicrobial and antibiofilm technology and its relevance to wound healing. Future Microbiol. 2015;10(2):255– 272. [10] Madeo J, Frieri M. Bacterial biofilms and chronic rhinosinusitis. Allergy Asthma Proc. 2013; Jul-Aug;34(4):335-41
[11]. Kilty SJ, Desrosiers MY. Are biofilms the answer in the pathophysiology and treatment of chronic rhinosinusitis? Immunol Allergy Clin North Am 2009; 29:645– 656. [12]. Hoiby N, Ciofu O, Johansen HK, et al. The clinical impact of bacterial biofilms. Int J Oral Sci 2011; 3:55– 65. [13]. Rajpaul K. Br J Biofilm in wound care. Community Nurs. 2015; Mar;Suppl Wound Care:S6, S8, S10-1. [14] Seth AK, Zhong A, Nguyen KT et al. Impact of a novel, antimicrobial dressing on in vivo, Pseudomonas aeruginosa wound biofilm: quantitative comparative analysis using a rabbit ear model. Wound Repair Regen. 2014 Nov-Dec;22(6):712-9. [15]. James GA, Zhao AG, Usui M et al. Microsensor and transcriptomic signatures of oxygen depletion in biofilms associated with chronic wounds. Wound Repair Regen. 2016; Jan 7 [16]. Fathabadie FF., Bayat M., Amini A.et al. Effects of pulsed infra-red low level-laser irradiation on mast cells number and degranulation in open skin wound healing of healthy and streptozotocin-induced diabetic rats. J Cosmet Laser Ther 2013;15:294–304. [17].AlGhamdi KM., Kumar A., Moussa NA. Low-level laser therapy: a useful technique for enhancing the proliferation of various cultured cells. Lasers Med Sci 2012;27:237–249. [18]. Pallotta RC., Bjordal JM., Frigo L, et al. Infrared (810-nm) low-level laser therapy on rat experimental knee inflammation. Lasers Med Sci 2012;27:71–78. [19]. Oliveira MC., Jr., Greiffo FR., Rigonato-Oliveira NC, et al. Low level laser therapy reduces acute lung inflammation in a model of pulmonary and extrapulmonary LPS-induced ARDS. J Photochem Photobiol B 2014;134:57–63. [20].Asghari S, Logsetty S, Liu S Imparting commercial antimicrobial dressings with lowadherence to burn wounds.Burns. 2016; Feb 1.
[21] Seo BF, Jung SN. The Immunomodulatory Effects of Mesenchymal Stem Cells in Prevention or Treatment of Excessive Scars. Stem Cells Int. 2016;2016:6937976. [22].Dyer DP, Thomson,JM Hermant A et al., “TSG-6 inhibits neutrophil migration via direct interaction with the chemokinen CXCL8, Journal of Immunology, 2014;. vol. 192, no. 5, pp. 2177–2185. [23] Thomsen K, Trøstrup H, Christophersen L et al.The phagocytic fitness of Leucopatches may impact the healing of chronic wounds. Clin Exp Immunol. 2016; Feb 27 [24] Gauglitz, GG Korting,HC PavicicT et al. Hypertrophic scarring and keloids: pathomechanisms and current and emerging treatment strategies,” Molecular Medicine, 2011; vol. 17, no. 1-2, pp. 113–124. [25] Gurtner GC, Werner, S Barrandon, Y et al., “Wound repair and regeneration,” Nature, 2008;vol. 453, no. 7193, pp. 314–321. [26]. Placik OJ , Lewis Jr.VL. Immunologic associations of keloids. Surgery, Gynecology & Obstetrics, 1992; vol. 175, no. 2, pp. 185–193. [27].Walmsley GG, Maan, ZN, Wong VW et al., Scarless wound healing: chasing the holy grail, Plastic and Reconstructive Surgery 2015;, vol. 135, no. 3, pp. 907–917. [28]. Smith RE, Strieter RM, . Phan SH et al, TNF and IL-6 mediate MIP-1ߙ expression in bleomycin-induced lung injury. Journal of Leukocyte Biology.1998;, vol. 64, no. 4, pp. 528–536, [29]. Satish L . Kathju S, Cellular and molecular characteristics of scarless versus fibrotic wound healing, Dermatology Research and Practice 2010; vol. Article ID 790234, 11 pages.. [30]. Nosbaum A, Prevel N, Truong HA et al. Cutting Edge: Regulatory T Cells Facilitate Cutaneous Wound Healing. J Immunol. 2016; Jan 29.
[31] Seo BF, Jung SN The Immunomodulatory Effects of Mesenchymal Stem Cells in Prevention or Treatment of Excessive Scars. Stem Cells Int. 2016;2016:6937976. [32]. Jeong JH. Adipose stem cells and skin repair. Curr Stem Cell Res Ther. 2010; Jun;5(2):137-40. [33]. Nie C, Yang D, Xu J et al. Locally administered adipose-derived stem cells accelerate wound healing through differentiation and vasculogenesis Cell Transplant. 2011;20(2):205-16. [34]. Hassan WU, Greiser U, Wang W.Role of adipose-derived stem cells in wound healing. Wound Repair Regen. 2014; May-Jun;22(3):313-25. [35] Kennelly R, Conneely JB, Bouchier-Hayes D et al.,Mast cells in tissue healing: from skin to the gastrointestinal tract. Curr Pharm Des. 2011; Nov;17(34):3772-5 [36].Cai C, Gill R, Eum HA, et al. Complement factor 3 deficiency attenuates hemorrhagic shock-related hepatic injury and systemic inflammatory response syndrome. Am J Physiol Regul Integr Comp Physiol. 2010;299:R1175eR1182. [37]. Shiota N, Nishikori Y, Kakizoe E, et al. Pathophysiological role of skin mast cells in wound healing after scald injury: study with mast cell deficient W/ W(V) mice. Int Arch Allergy Immunol. 2010;151:80e88 [38] Younan G, Suber F, Xing W, et al. The inflammatory response after an epidermal burn depends on the activities of mouse mast cell proteases 4 and 5. J Immunol. 2010;185:7681e7690). .[39]. Johnston BR, Ha AY, Kwan D Surgical Management of Chronic Wounds. R I Med J (2013). 2016; Feb 1;99(2):28-31.
[40]. Giannoni-Pastor A, Eiroa-Orosa FJ, Fidel Kinori SG et al. Prevalence and Predictors of Posttraumatic Stress Symptomatology Among Burn Survivors: A Systematic Review and MetaAnalysis.J Burn Care Res. 2016; Jan-Feb;37(1):e79-89) [41].Stella M, Castagnoli C, Gangemi EN Postburn scars: an update. Int J Low Extrem Wounds. 2008; Sep;7(3):176-81. [42] Costa RA, Ruiz-de-Souza V, Azevedo GM Jr, et al Indirect effects of oral tolerance improve wound healing in skin.Wound Repair Regen. 2011; Jul-Aug;19(4):487-97 [43].Saeman MR,,Hodgman EI, Burris A et al. Epidemiology and outcomes of pediatric burns over 35 years at Parkland Hospital. Burns. 2015; Nov 21. [44]. Abdul-Muneer PM, Pfister BJ, Haorah J et al. Role of Matrix Metalloproteinases in the Pathogenesis of Traumatic Brain Injury Mol Neurobiol. 2015; Nov 5. [45].Gebhard F, Pfetsch H, Steinbach G, et al. Interleukin 6 an early marker of injury severity following major trauma in humans? Arch Surg. 2000;135: 291e295 [46].Neidhardt R, Keel M, Steckholzer U, et al. Relationship of interleukin-10 plasma levels to severity of injury and clinical outcome in injured patients.J Trauma. 1997;42:863e870. [47].Stensballe J, Christiansen M, Tønnesen E, et al. The early IL-6 and IL-10 response in trauma is correlated with injury severity and mortality. Acta Anaesthesiol Scand. 2009;53:515e521. [48].Hietbrink F, Koenderman L, Rijkers GT, Leenen L.l. Trauma: the role of the innate immune system. World Journal of Emergency Surgery. 2006.. [49] Hazeldine J, Hampson P, Lord JM The impact of trauma on neutrophil function Injury 2014;. Dec;45(12):1824-33
[50]. Tsukamoto T, Chanthaphavong RS, Pape HC Current theories on the pathophysiology of multiple organ failure after trauma. Injury 2010;.Jan;41(1):21-6.. [51] Frieri M, Kumar K, Boutin A.Review: Immunology of sinusitis, trauma, asthma, and sepsis. Allergy Rhinol (Providence). 2015; Jan;6(3):205-14. [52].Frieri M, Kumar K, Boutin A.Role of mast cells in trauma and neuroinflammation in allergy immunology.Ann Allergy Asthma Immunol. 2015; Sep;115(3):172-7. .